* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With copper(I) bromide In N,N-dimethyl-formamide at 130℃; for 24 h; Inert atmosphere
10g of 4-bromophenylacetic acid was added to 20 mL of DMF, 20 mL of DMF was added, 5.0 g of sodium methanethiol was added,Copper 0.5g, nitrogen replacement, stirring to increase the reaction temperature to 130 ° C under nitrogen protection, stirring reaction 24 hours, cooling reactionAnd the remainder were the same as in Example 1 of the present invention, and the yield was 79.3percent.; Taking 4- bromobenzene acetic acid 10g in 100 ml in three-mouth bottle, by adding DMF20mL, adding a thiol sodium 5.0g, adding cuprous bromide 0.1g, after the replacement of nitrogen, to improving the reaction temperature under stirring 130 °C, under the protection of nitrogen stirring for 4 hours, cooling the reaction liquid, by adding 40percent NaOH5mL, stirring 10 minutes. Cooling the reaction liquid, by adding ethyl acetate 25 ml extraction two, by adding ethyl acetate in 50 ml, by adding 10percent dilute sulfuric acid adjusted to pH 2-4, collecting ethyl acetate, ethyl acetate with water 10 ml after washing, distillation of the ethyl acetate to 20 ml left and right, by adding hexane 20 ml, raise the reaction temperature to reflux, after to be solid entirely dissolved, a slow cooling to room temperature, filtered, scaled to obtain yellowish crystalline, to obtain a target product after drying 6.38g, yield 76.1percent.
Reference：
[1] Patent: CN105646306, 2016, A, . Location in patent: Paragraph 0011
2
[ 5188-07-8 ]
[ 1878-68-8 ]
[ 16188-55-9 ]
Yield
Reaction Conditions
Operation in experiment
76.1%
With copper(I) bromide In N,N-dimethyl-formamide at 130℃; Inert atmosphere
Taking 4- bromobenzene acetic acid 10g in 100 ml in three-mouth bottle, by adding DMF20mL, adding a thiol sodium 5.0g, adding cuprous bromide 0.1g, after the replacement of nitrogen, to improving the reaction temperature under stirring 130 °C, under the protection of nitrogen stirring for 4 hours, cooling the reaction liquid, by adding 40percent NaOH5mL, stirring 10 minutes. Cooling the reaction liquid, by adding ethyl acetate 25 ml extraction two, by adding ethyl acetate in 50 ml, by adding 10percent dilute sulfuric acid adjusted to pH 2-4, collecting ethyl acetate, ethyl acetate with water 10 ml after washing, distillation of the ethyl acetate to 20 ml left and right, by adding hexane 20 ml, raise the reaction temperature to reflux, after to be solid entirely dissolved, a slow cooling to room temperature, filtered, scaled to obtain yellowish crystalline, to obtain a target product after drying 6.38g, yield 76.1percent.
Reference：
[1] Patent: CN105646306, 2016, A, . Location in patent: Paragraph 0010
3
[ 53066-99-2 ]
[ 16188-55-9 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2017, vol. 359, # 15, p. 2682 - 2691
[2] Patent: EP975596, 2004, B1, . Location in patent: Page 10
4
[ 38746-92-8 ]
[ 16188-55-9 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2009, vol. 44, # 2, p. 551 - 557
[2] Patent: US5270313, 1993, A,
[3] Journal of Chemical Crystallography, 2010, vol. 40, # 1, p. 25 - 28
5
[ 1778-09-2 ]
[ 16188-55-9 ]
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1990, vol. 55, # 1, p. 97 - 118
[2] Bulletin of the Chemical Society of Japan, 2009, vol. 82, # 2, p. 254 - 260
6
[ 1798-06-7 ]
[ 4856-13-7 ]
[ 16188-55-9 ]
Reference：
[1] Tetrahedron, 1978, vol. 34, p. 2767 - 2773
7
[ 100-68-5 ]
[ 16188-55-9 ]
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1990, vol. 55, # 1, p. 97 - 118
With tert-butylmagnesium chloride In tetrahydrofuran at 65 - 70℃; for 1 h;
To the reaction flask was added llg (4-methylthio) phenylacetic acid,200 mL of anhydrous THF, and the mixture was heated to 65-70 ° C.Maintain T = 65-70 ° C while dropping175 Mll. 0 M t-BuMgCl in THF and5.7g6-methylpyridine-3-carboxylate50 ml of THF solution. Dropping to complete the incubation reaction for 1 hour.Cooling to room temperature, dropping 50ml4M hydrochloric acid quenching reaction, stratification, organic layer and then 50ml4M hydrochloric acid extraction,The aqueous layer was added and the aqueous layer was added with 50 g of sodium hydroxide,Heated to 40-50 ° C for 3 hours, cooled to room temperature,Filtration gave 6.9 g of a pale yellow solid, 72.0percent yield, 97.3percent pure
73A. ethyl 2-(4-(methylthio)phenyl)acetate A mixture of <strong>[16188-55-9]2-(4-(methylthio)phenyl)acetic acid</strong> (10.8 g, 60 mmol) and concentrated sulfuric acid (1 ML) in ethanol (150 ML) was refluxed for 8 hours.. The reaction mixture was concentrated in vacuo, and the residue dissolved in ethyl ether.. The ether solution was washed with 10% sodium bicarbonate, brine, dried over anhydrous MgSO4, and concentrated in vacuo to provide the ethyl ester (yield: 12.1 g; 96%).
With sulfuric acid; at 100℃; for 26h;
Step A: Preparation of Ethyl 2-(4-(methylthio)phenyl)acetate; [0487] A mixture of 4-(methylthio)phenylacetic acid (5.10 g, 28.0 mmol) and H2SO4 (0.155 mL, 2.80 mmol) in EtOH (150 mL) in a 500 mL round bottom flask, were stirred at 1000C for 26 hours. The reaction was concentrated in vacuo, diluted with EtOAc (200 mL), washed with deionized water (2 x 150 mL), and then with brine (100 mL). The organic layer was dried over MgSO4, concentrated, and dried in vacuo. The crude product was purified by flash column chromatography (silica, 0-20% EtOAc in hexane) to give the title compound (5.95 g). MS m/e = 21 1 (M+H)+.
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 4h;
Step 1: Oxalyl chloride (0.84 mL, 9.6 mmol) was added dropwise to stirred solution of <strong>[16188-55-9]4-methylsulfanyl-phenylacetic acid</strong> (1.5 g, 8.2 mmol) in dichloromethane (20 mL) containing one drop of dimethylformamide. The reaction mixture was stirred at room temperature for 4 hours, and was then evaporated under reduced pressure to afford crude 4-methylsulfanyl-phenylacetyl chloride, which was used without further purification
With sodium periodate; In methanol; water; at 0 - 20℃; for 2h;
[00196] To a solution of 2-(4-(methylthio) phenyl) acetic acid (1.0 g, 5.49 mmol) in MeOH (10 ml.) was added with Nal04 (1.3 g, 6.04 mmol) in H20 (10 ml.) at 0 C. After addition, the mixture was stirred at 20 C for 2 h. The reaction mixture was filtered, concentrated to afford 2-(4- (methylsulfinyl)phenyl) acetic acid Core-1 b_E1 (0.9 g, yield 82%) as white solid, which was used directly in the next step; LC-MS Rt 0.204 min, MS m/z [M+H]+ 199.0; Method 3.
With sodium tungstate; dihydrogen peroxide; Aliquat 336; In water; ethyl acetate; for 0.5h;
[15.1] [] 4-(Methylthio)phenylacetic acid 4 (FW=182.3)(0.402mol)Na2WO4? H2O (FW=329.9)2.64g (0.008mol)Aliquat 336 (FW=404)8.08g (0.020mol)Hydrogen peroxide (FW=34.0, 30wt% in water)136g (1.200mol,123mL) A flask equipped for mechanical stirring was charged with 3 (from reaction above, in EtOAc), Aliquat 336, and Na2WO4? 2H2O (dissolved in ca. 15mL H2O). Hydrogen peroxide was added slowly via an addition funnel over ca. 30 min. Completion of reaction was checked by HPLC. The reaction was washed with 2 x 400mL H2O and dried over MgSO4. Quantification of product in the organic layer gave 61.29g 5 (71% yield from thioanisole). On concentration of the solution, a white solid precipitated. The slurry was filtered, and washed with hexanes. Recovery was 49.02g 5 (57% from thioanisole).
[14.1] [] 3 (in 1N NaOH solution)(0.402mol)Hydrazine (FW=32.1, 35wt% in water)206.14g (2252mol, 204mL)NaOH (5N solution)5mL The hydrazine and NaOH were charged to a Morton flask equipped with mechanical stirring. After heating the hydrazine solution to 75C, the solution of 3 in NaOH was added over 35-40 min. At the end of the addition the reaction mixture was brought to reflux for 5 days. HPLC showed the reaction to be ca. 95% complete at this point. The starting material was largely consumed in under 24 h, but a third peak which took several days to convert to 4. The reaction was acidified with concentrated HCl to pH=1.5 and extracted with EtOAc (1 x 750mL and 1 x 250mL). The combined product-containing organic phases were washed 2 x 250mL 1N HCl. On acidification, the reaction mixture turned bright yellow.
(A) N-(1H-Benzoimidazol-2-yl)-2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide A solution of 4-(methylthio)phenylacetic acid (6.91 g, 37.9 mmol) in methanol (100 mL) was treated slowly with concentrated sulfuric acid (1 mL). The resulting reaction mixture was heated under reflux for 19 h. The reaction mixture was allowed to cool to 25 C. and then concentrated in vacuo to remove methanol. The resulting residue was diluted with ethyl acetate (200 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (3*300 mL) and a saturated aqueous sodium chloride solution (1*100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford (4-methylsulfanyl-phenyl)-acetic acid methyl ester (7.28 g, 98%) as a yellow liquid which was used without further purification: EI-HRMS m/e calcd for C10H12O2S (M+) 196.0558, found 196.0559.
98%
With sulfuric acid; In methanol;
(A) 2-(3-Bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrimidin-4-yl-propionamide A solution of 4-(methylthio)phenylacetic acid (6.91 g, 37.9 mmol) in methanol (100 mL) was treated slowly with concentrated sulfuric acid (1 mL). The resulting reaction mixture was heated under reflux for 19 h. The reaction mixture was allowed to cool to 25 C. and then concentrated in vacuo to remove methanol. The resulting residue was diluted with ethyl acetate (200 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (3*300 mL) and a saturated aqueous sodium chloride solution (1*100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford (4-methylsulfanyl-phenyl)-acetic acid methyl ester (7.28 g, 98%) as a yellow liquid which was used without further purification: EI-HRMS m/e calcd for C10H12O2S (M+) 196.0558, found 196.0559.
92%
With sulfuric acid; In methanol;
EXAMPLE 73 2-(3-Bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide A solution of 4-(methylthio)phenylacetic acid (21.21 g, 116.38 mmol) in methanol (291 mL) was treated slowly with concentrated sulfuric acid (3 mL). The resulting reaction mixture was heated under reflux for 3 d. The reaction mixture was allowed to cool to 25 C. and then concentrated in vacuo to remove methanol. The resulting residue was diluted with diethyl ether (600 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (3*300 mL) and a saturated aqueous sodium chloride solution (1*300 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford (4-methylsulfanyl-phenyl)-acetic acid methyl ester (20.95 g, 92%) as a yellow liquid which was used without further purification: EI-HRMS m/e calcd for C10H12O2S (M+) 196.0558, found 196.0559.
92%
With sulfuric acid; In methanol;
EXAMPLE 74 2-(3-Bromo-4-methanesulfonyl-phenyl)-N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-propionamide A solution of 4-(methylthio)phenylacetic acid (21.21 g, 116.38 mmol) in methanol (291 mL) was treated slowly with concentrated sulfuric acid (3 mL). The resulting reaction mixture was heated under reflux for 3 d. The reaction mixture was allowed to cool to 25 C. and then concentrated in vacuo to remove methanol. The resulting residue was diluted with diethyl ether (600 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (3*300 mL) and a saturated aqueous sodium chloride solution (1*300 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford (4-methylsulfanyl-phenyl)-acetic acid methyl ester (20.95 g, 92%) as a yellow liquid which was used without further purification: EI-HRMS m/e calcd for C10H12O2S (M+) 196.0558, found 196.0559.
92%
With sulfuric acid; In methanol;
EXAMPLE 75 2-(3-Cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide A solution of 4-(methylthio)phenylacetic acid (21.21 g, 116.38 numol) in methanol (291 mL) was treated slowly with concentrated sulfuric acid (3 mL). The resulting reaction mixture was heated under reflux for 3 d. The reaction mixture was allowed to cool to 25 C. and then concentrated in vacuo to remove methanol. The resulting residue was diluted with diethyl ether (600 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (3*300 mL) and a saturated aqueous sodium chloride solution (1*300 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford (4-methylsulfanyl-phenyl)-acetic acid methyl ester (20.95 g, 92%) as a yellow liquid which was used without further purification: EI-HRMS m/e calcd for C10H12O2S (M+) 196.0558, found 196.0559.
92%
With sulfuric acid; In methanol;
EXAMPLE 76 2-(3-Cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide A solution of 4-(methylthio)phenylacetic acid (21.21 g, 116.38 mmol) in methanol (291 mL) was treated slowly with concentrated sulfuric acid (3 mL). The resulting reaction mixture was heated under reflux for 3 d. The reaction mixture was allowed to cool to 25 C. and then concentrated in vacuo to remove methanol. The resulting residue was diluted with diethyl ether (600 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (3*300 mL) and a saturated aqueous sodium chloride solution (1*300 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford (4-methylsulfanyl-phenyl)-acetic acid methyl ester (20.95 g, 92%) as a yellow liquid which was used without further purification: EI-HRMS m/e calcd for C10H12O2S (M+) 196.0558, found 196.0559.
92%
With sulfuric acid; In methanol;
Example 26 N-Benzothiazol-2-yl-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide A solution of 4-(methylthio)phenylacetic acid (21.21 g, 116.38 mmol) in methanol (291 mL) was treated slowly with concentrated sulfuric acid (3 mL). The resulting reaction mixture was heated under reflux for 3 d. The reaction mixture was allowed to cool to 25 C. and then concentrated in vacuo to remove methanol. The resulting residue was diluted with diethyl ether (600 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (3*300 mL) and a saturated aqueous sodium chloride solution (1*300 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford (4-methylsulfanyl-phenyl)-acetic acid methyl ester (20.95 g, 92%) as a yellow liquid which was used without further purification: EI-HRMS m/e calcd for C10H12O2S (M+) 196.0558, found 196.0559.
92%
With sulfuric acid; In methanol;
EXAMPLE 72 2-(3-Bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide A solution of 4-(methylthio)phenylacetic acid (21.21 g, 116.38 mmol) in methanol (291 mL) was treated slowly with concentrated sulfuric acid (3 mL). The resulting reaction mixture was heated under reflux for 3 d. The reaction mixture was allowed to cool to 25 C. and then concentrated in vacuo to remove methanol. The resulting residue was diluted with diethyl ether (600 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (3*300 mL) and a saturated aqueous sodium chloride solution (1*300 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford (4-methylsulfanyl-phenyl)-acetic acid methyl ester (20.95 g, 92%) as a yellow liquid which was used without further purification: EI-HRMS m/e calcd for C10H12O2S (M+) 196.0558, found 196.0559.
With n-butyllithium; diisopropylamine; In tetrahydrofuran;
EXAMPLE 9 3-Cyclopentyl-2-(4-methylsulfanyl-phenyl)-N-thiazol-2-yl-propionamide A solution of diisopropylamine (3.2 mL, 23.16 mnmol) in dry tetrahydrofuran (10.3 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3.4 mL) was cooled to -78 C. under nitrogen and then treated with a lOM solution of n-butyllithium in hexanes (2.3 mL, 23.16 mmol). The resulting reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of 4-(methylthio)phenylacetic acid (2.01 g, 11.03 mmol) in dry tetrahydrofuran (10.3 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3.4 mL). The reaction mixture was allowed to stir at -78 C. for 1 h, at which time, a solution of iodomethylcyclopentane (2.55 g, 12.13 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was stirred at -78 C. for 30 min and then allowed to warm to 25 C. where it was stirred for 24 h. The reaction mixture was quenched with water and then concentrated in vacuo to remove tetrahydrofuran. The remaining aqueous phase was acidified to pH=2 with a 10% aqueous hydrochloric acid solution and then extracted with ethyl acetate (200 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1*100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)propionic acid (1.01 g, 35%) as a cream solid: mp 91-93 C.; EI-HRMS m/e calcd for C15H20O2S (M+) 264.1184, found 264.1177.
35%
With n-butyllithium; diisopropylamine; In tetrahydrofuran;
EXAMPLE 61 3-Cyclopentyl-2-(4-methanesulfinyl-phenyl)-N-thiazol-2-yl-propionamide A solution of diisopropylamine (3.2 mL, 23.16 mmol) in dry tetrahydrofuran (10.3 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3.4 mL) was cooled to -78 C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (2.3 mL, 23.16 mmol). The resulting reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of 4-(methylthio)phenylacetic acid (2.01 g, 11.03 mmol) in dry tetrahydrofuran (10.3 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3.4 mL). The reaction mixture was allowed to stir at -78 C. for 1 h, at which time, a solution of iodomethylcyclopentane (2.55 g, 12.13 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was stirred at -78 C. for 30 min and then allowed to warm to 25 C. where it was stirred for 24 h. The reaction mixture was quenched with water and then concentrated in vacuo to remove tetrahydrofuran. The remaining aqueous phase was acidified to pH=2 with a 10% aqueous hydrochloric acid solution and then extracted with ethyl acetate (1*200 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1*100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)propionic acid (1.01 g, 35%) as a cream solid: mp 91-93 C.; EI-HRMS m/e calcd for C15H20O2S (M+) 264.1184, found 264.1177.
35%
With n-butyllithium; diisopropylamine; In tetrahydrofuran;
(A) N-Benzothiazol-2-yl-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionamide A solution of diisopropylamine (3.2 mL, 23.16 mmol) in dry tetrahydrofuran (10.3 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3.4 mL) was cooled to -78 C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (2.3 mL, 23.16 mmol). The resulting reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of 4-(methylthio)phenylacetic acid (2.01 g 11.03 mmol) in dry tetrahydrofuran (10.3 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3.4 mL). The reaction mixture was allowed to stir at -78 C. for 1 h, at which time, a solution of iodomethylcyclopentane (2.55 g, 12.13 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was stirred at -78 C. for 30 min and then allowed to warm to 25 C. where it was stirred for 24 h. The reaction mixture was quenched with water and then concentrated in vacuo to remove tetrahydrofuran. The remaining aqueous phase was acidified to pH=2 with a 10% aqueous hydrochloric acid solution and then extracted with ethyl acetate (200 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1*100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)propionic acid (1.01 g, 35%) as a cream solid: mp 91-93 C.; EI-HRMS m/e calcd for C15H20S (M+) 264.1184, found 264.1177.
35%
With n-butyllithium; diisopropylamine; In tetrahydrofuran;
EXAMPLE 9 3-Cyclopentyl-2-(4-methylsulfanyl-phenyl)-N-thiazol-2-yl-propionamide A solution of diisopropylamine (3.2 mL, 23.16 mmol) in dry tetrahydrofuran (10.3 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3.4 mL) was cooled to -78 C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (2.3 mL, 23.16 mmol). The resulting reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of 4-(methylthio)phenylacetic acid (2.01 g, 11.03 mmol) in dry tetrahydrofuran (10.3 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3.4 mL). The reaction mixture was allowed to stir at -78 C. for 1 h, at which time, a solution of iodomethylcyclopentane (2.55 g, 12.13 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was then stirred at -78 C. for 30 min and then allowed to warm to 25 C. where it was stirred for 24 h. The reaction mixture was quenched with water and then concentrated in vacuo to remove tetrahydrofuran. The remaining aqueous phase was acidified to pH=2 with a 10% aqueous hydrochloric acid solution and then extracted with ethyl acetate (1*200 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1*100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)propionic acid (1.01 g, 35%) as a cream solid: mp 91-93 C.; EI-HRMS m/e calcd for C15H20O2S (M+) 264.1184, found 264.1177.
35%
With n-butyllithium; diisopropylamine; In tetrahydrofuran;
EXAMPLE 134 2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazole-5-carboxylic acid amide A solution of diisopropylamine (3.2 mL, 23.16 mmol) in dry tetrahydrofuran (10.3 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3.4 mL) was cooled to -78 C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (2.3 mL, 23.16 mmol). The resulting reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of 4-(methylthio)phenylacetic acid (2.01 g, 11.03 mmol) in dry tetrahydrofuran (10.3 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3.4 mL). The reaction mixture was allowed to stir at -78 C. for 1 h, at which time, a solution of iodomethylcyclopentane (2.55 g, 12.13 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was then stirred at -78 C. for 30 min and then allowed to warm to 25 C. where it was stirred for 24 h. The reaction mixture was quenched with water and then concentrated in vacuo to remove tetrahydrofuran. The remaining aqueous phase was acidified to pH=2 with a 10% aqueous hydrochloric acid solution and then extracted with ethyl acetate (200 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1*100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)propionic acid (1.01 g, 35%) as a cream solid: mp 91-93 C.; EI-HRMS m/e calcd for C15H20O2S (M+) 264.1184, found 264.1177.
35%
With n-butyllithium; diisopropylamine; In tetrahydrofuran;
EXAMPLE 61 3-Cyclopentyl-2-(4-methanesulfinyl-phenyl)-N-thiazol-2-yl-propionamide A solution of diisopropylamine (3.2 mL, 23.16 mmol) in dry tetrahydrofuran (10.3 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3.4 mL) was cooled to -78 C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (2.3 mL, 23.16 mmol). The resulting reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of 4-(methylthio)phenylacetic acid (2.01 g, 11.03 mmol) in dry tetrahydrofuran (10.3 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3.4 mL). The reaction mixture was allowed to stir at -78 C. for 1 h, at which time, a solution of iodomethylcyclopentane (2.55 g, 12.13 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was then stirred at -78 C. for 30 min and then allowed to warm to 25 C. where it was stirred for 24 h. The reaction mixture was quenched with water and then concentrated in vacuo to remove tetrahydrofuran. The remaining aqueous phase was acidified to pH=2 with a 10% aqueous hydrochloric acid solution and then extracted with ethyl acetate (1*200 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1*100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)propionic acid (1.01 g, 35%) as a cream solid: mp 91-93 C.; EI-HRMS m/e calcd for C15H20O2S (M+) 264.1184, found 264.1177.
With potassium carbonate; In tetrahydrofuran; water; toluene;
EXAMPLE 126 3-Cyclopentyl-2(R)-(4-methylsulfanyl-phenyl)-N-pyrazin-2-yl-propionamide A mixture of 4-(methylthio)phenylacetic acid (50 g, 272 mmol) in tetrahydrofuran (250 mL) was treated with freshly powdered potassium carbonate (93.8 g, 679 mmol). A very mild exotherm ensued, and the resulting white suspension was stirred at 25-26 C. for 30 min. The reaction mixture was then cooled to -10 C. and treated with trimethylacetyl chloride (35.5 mL, 285 mmol) over 30 min. After completion of the addition, the reaction mixture was then stirred at -10 C. to -5 C. for 30 min and then treated with (1R,2R)-(-)-pseudoephedrine (59.5 g, 353 mmol) in portions over 15 min while maintaining the temperature of the reaction mixture between -10 C. and -4 C. The reaction mixture was then stirred at -7 C. to 0 C. for 3 h. The reaction mixture was then quenched at 0 C. by the addition of water (150 mL). After vigorously stirring for 10 min, toluene (150 mL) was added, and the reaction mixture was stirred for 5 min. The organic layer was separated and washed with water (2*100 mL). The combined aqueous layers were back-extracted with toluene (1*50 mL). The combined organic layers were washed with a 1N aqueous sulfuric acid solution (1*200 mL), a saturated aqueous sodium bicarbonate solution (1*200 mL), and a solution of water/saturated aqueous sodium chloride solution (1:1, 1*50 mL). The resulting organic layer was then concentrated in vacuo to afford a white solid. This white solid was dried overnight under high vacuum (0.4 mm Hg) to afford crude N-[2(R)-hydroxy-1(R)-methyl-2(R)-phenyl-ethyl]-N-methyl-2-(4-methylsulfanyl-phenyl)-acetamide (82.8 g, 92.6% pure by HPLC analysis). This material was dissolved in toluene (225 mL) at reflux. After standing in a refrigerator over the weekend, the resulting crystalline material was collected by filtration, washed with cold toluene (3*35 mL), and dried under high vacuum to afford N-[2(R)-hydroxy-1(R)-methyl-2(R)-phenyl-ethyl]-N-methyl-2-(4-methylsulfanyl-phenyl)-acetamide (66.1 g, 73.1%) as white crystals: mp 112-113 C.; 99.6% pure by HPLC analysis. HPLC conditions as follows:
N-methoxy-N-methyl-4-(methylthio)benzeneacetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
In dichloromethane;
Step 1. Preparation of N-methoxy-N-methyl-4-(methylthio)benzeneacetamide To a solution of 4-(methylthio)phenylacetic acid (18.3 g, 0.100 mol) in methylene chloride (200 mL) was added 1,1'-carbonyldiimidazole (16.3 g, 0.100 mol) portionwise. The mixture was stirred at room temperature for 20 minutes, and N,O-dimethylhydroxylamine hydrochloride (9.8 g, 0.100 mol) was added. The reaction mixture was stirred overnight at room temperature, diluted with ether (500 mL) and washed successively with 1N hydrochloric acid, saturated aqueous sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated in vacuo to give 20.9 g of N-methoxy-N-methyl-4-(methylthio)-benzeneacetamide as a clear oil (93%).
With sodium hydroxide; In ethylene glycol; ethyl acetate;
12 g of (p-methylthio)benzyl cyanide were dissolved in 30 ml of ethylene glycol and treated with 9 g of NaOH (as a 30% solution). The reaction mixture was stirred at 140 C. for 3 hours. After cooling to room temperature the mixture was acidified with 25% hydrochloric acid, the precipitate was taken up in ethyl acetate and extracted with water. There were obtained 11.5 g of (p-methylthio)phenylacetic acid; melting point 94-96 C.
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